The long term objectives of this proposal are to gain an understanding of the mechanism(s) of the immunosuppressive activity of the marijuana component delta-9-tetrahydrocannabinol (THC). The specific aims are to determine the cellular and molecular mechanisms by which THC inhibits the natural killer (NK) cell, lymphocyte blastogenesis and macrophage phagocytic activities of human peripheral blood leukocytes, although the study will initially focus on NK cell cytotoxicity. By doing so, an understanding of ways in which this type of immune suppression can be reversed by intervention with immunostimulatory substances, such as interleukin 2 can be acquired. Also, with regard to the immunosuppressive activity of THC these studies are intended to determine if marijuana might contribute to the onset of overt AIDS in individuals infected by the human immunodeficiency virus (HIV). These goals will be reached by studying the importance of cytokines (or their absence) in the mediation of THC induced suppression, examining the function of metabolic pathways known to be involved in lymphocyte and macrophage activation, and examining whether leukocytes from HIV infected individuals are more severely depressed in immune reactivity and produce greater numbers of infectious HIV. Ultimately, the goal is to overcome all of the detrimental effects of THC using immunomodulatory substances.